Dr. Manners

Good manners make a difference—in science and elsewhere. This includes our social media etiquette as researchers. Subject Categories: S&S: History & Philosophy of Science, Methods & Resources, S&S: Ethics

Elbows off the table, please. Don’t chew with your mouth open. Don’t blow your nose at the table. Don’t put your feet up on the chair or table. And please, do not yuck my yum. These are basic table manners that have come up at some of our lab meals, and I have often wondered if it was my job to teach my trainees social graces. A good fellow scientist and friend of mine once told me it was absolutely our place as mentors to teach our trainees not only how to do science well, but also how to be well‐mannered humans. While these Emily Post‐approved table manners might seem old‐fashioned (I’m guessing some readers will have to look up Emily Post), I strongly believe they still hold a place in modern society; being in good company never goes out of style.Speaking of modern society: upon encouragement by several of my scientist friends, I joined Twitter in 2016. My motivation was mainly to hear about pre‐prints and publications, conference announcements and relevant news, science or otherwise. I also follow people who just make me laugh (I highly recommend @ConanOBrien or @dog_rates). I (re)tweet job openings, conference announcements, and interesting new data. Occasionally, I post photos from conferences, or random science‐related art. I also appreciate the sense of community that social media brings to the table. However, social media is a venue where I have also seen manners go to die. Rapidly.It is really shocking to read what some people feel perfectly comfortable tweeting. While most of us can agree that foul language and highly offensive opinions are generally considered distasteful, there are other, subtler but nonetheless equally—if not more—cringe‐worthy offenses online when I am fairly certain these people would never utter such words in real life. In the era of pandemic, the existence of people tweeting about not being able to eat at their favorite restaurant or travel to some destination holiday because of lockdown shows an egregious lack of self‐awareness. Sure it sucks to cancel a wedding due to COVID‐19, but do you need to moan to your followers—most of whom are likely total strangers—about it while other people have lost their jobs? If I had a nickel for every first‐world complaint I have seen on Twitter, I’d have retired a long time ago; although to be honest, I would do science for free. However, these examples pale in comparison with another type of tweeter: Reader, I submit to you, “the Humblebragger.”From the MacMillan Buzzword dictionary (via Google): a humblebrag is “a statement in which you pretend to be modest but which you are really using as a way of telling people about your success or achievements.” I would further translate this definition to indicate that humblebraggers are starved for attention. After joining Twitter, I quickly found many people using social media to announce how “humble and honored” they are for receiving grant or prize X, Y, or Z. In general, these are junior faculty who have perhaps not acquired the self‐awareness more senior scientists have. Perhaps the most off‐putting posts I have seen are from people who post photos of their NIH application priority scores right after study section, or their Notice of Awards (NOA). When did we ever, before social media, send little notes to each other—let alone to complete strangers—announcing our priority scores or NOAs? (Spoiler: NEVER)Some of you reading this opinion piece might have humblebragged at one or time or another, and might not understand why it is distasteful. Please let me explain. For every person who gets a fundable score, there are dozens more people who do not, and they are sad (I speak from many years of experience). While said fundable‐score person might be by someone we like—and I absolutely, positively wish them well—there are many more people who will feel lousy because they did not get funding from the same review round. When has anyone ever felt good about other people getting something that they, too, desire? I think as children, none of us liked the kid on the playground who ran around with the best new Toy of the Season. As adults, do we feel differently? Along these lines, I have never been a fan of “best poster/talk/abstract” prizes. Trainees should not be striving for these fleeting recognitions and should focus on doing the best science for Science’s sake; I really believe this competition process sets people up for life in a negative way—there, I’ve said it.Can your friends and colleagues tweet about your honors? Sure, why not, and by all means please let your well‐wishers honor you, and do thank them and graciously congratulate your trainees or colleagues for helping you to get there. But to post things yourself? Please. Don’t be surprised if you have been muted by many of your followers.It is notable that many of our most decorated scientists are not on Twitter, or at least never tweet about their accomplishments. I do not recall ever seeing a single Nobel laureate announce how humbled and honored they are about their prize. Of course, I might be wrong, but I am willing to bet the numbers are much lower than what I have observed for junior faculty. True humility will never be demonstrated by announcing your achievements to your social media followers, and I believe humblebragging reveals insecurity more than anything. I hope that many more of us can follow the lead of our top scientists both in creativity, rigor, and social media politeness.     

Fifteen compelling open questions in plant cell biology

As scientists, we are at least as excited about the open questions—the things we do not know—as the discoveries. Here, we asked 15 experts to describe the most compelling open questions in plant cell biology. These are their questions: How are organelle identity, domains, and boundaries maintained under the continuous flux of vesicle trafficking and membrane remodeling? Is the plant cortical microtubule cytoskeleton a mechanosensory apparatus? How are the cellular pathways of cell wall synthesis, assembly, modification, and integrity sensing linked in plants? Why do plasmodesmata open and close? Is there retrograde signaling from vacuoles to the nucleus? How do root cells accommodate fungal endosymbionts? What is the role of cell edges in plant morphogenesis? How is the cell division site determined? What are the emergent effects of polyploidy on the biology of the cell, and how are any such “rules” conditioned by cell type? Can mechanical forces trigger new cell fates in plants? How does a single differentiated somatic cell reprogram and gain pluripotency? How does polarity develop de-novo in isolated plant cells? What is the spectrum of cellular functions for membraneless organelles and intrinsically disordered proteins? How do plants deal with internal noise? How does order emerge in cells and propagate to organs and organisms from complex dynamical processes? We hope you find the discussions of these questions thought provoking and inspiring.

We asked 15 experts to address what they consider to be the most compelling open questions in plant cell biology and these are their questions.     

Science Educational Outreach Programs That Benefit Students and Scientists

Both scientists and the public would benefit from improved communication of basic scientific research and from integrating scientists into education outreach, but opportunities to support these efforts are limited. We have developed two low-cost programs—"Present Your PhD Thesis to a 12-Year-Old" and "Shadow a Scientist”—that combine training in science communication with outreach to area middle schools. We assessed the outcomes of these programs and found a 2-fold benefit: scientists improve their communication skills by explaining basic science research to a general audience, and students'' enthusiasm for science and their scientific knowledge are increased. Here we present details about both programs, along with our assessment of them, and discuss the feasibility of exporting these programs to other universities.     

On Leukocytes in Mammary Development and Cancer

During metastasis, tumor cells may be copying a program that is executed by hematopoietic stem cells during development.That cancer is development gone awry is not a new concept. Most of the “hallmarks” ascribed to cancer—proliferation, invasion and induction of blood vessel growth—also occur during organogenesis and development. Therefore, tumors are not necessarily learning new tricks during their development, but how about when they metastasize? In colonizing a new organ, often with some degree of specificity, tumor cells may simply be copying a program that is executed during development by hematopoietic stem cells (HSCs)—the stem cells that ultimately generate all of the cells in our blood and maintain its homeostasis. One family of cells generated by HSCs—leukocytes—is the focus of the work by Coussens and Pollard (2012). These two scientists have woven together several studies that revolutionized the way we think of immune cells. As pointed out by the investigators (whose respective laboratories are responsible for much of the seminal work on this subject), immune cells also have a variety of trophic functions, and it is these functions that are used rationally during development, and recklessly during tumor growth.This leads us back to metastasis. There is so much to learn about why a tumor travels from one organ to another, how it does so, and the manner by which it adapts to and ultimately flourishes (or fails) in a foreign microenvironment. And as stated above, immune cell precursors, HSCs, do the same. In the mouse, HSCs have originated in one tissue (the dorsal aorta), traveled to another (the placenta) via the circulation, and matured somewhere else (the liver)—all before birth. Finally, HSCs make their way to the bone marrow, where they reside postnatally. Specialized niches in the bone marrow are thought to mediate HSC dormancy as a means to preserve the “stemness” of this population, and there are mechanisms in place that allow these cells to rapidly exit these environs and proliferate in response to injury. Therefore, it should not come as a surprise that a common site where micrometastases are found is the bone marrow for many cancers (including that of the breast).Uncovering whether the same niches that control HSC expansion in the bone marrow are also responsible for maintaining quiescence of tumor cell populations is an exciting prospect, as is deciphering the precise components of these niches. Such work could explain the seemingly incongruous observation that despite an absence of clinically detectable disease, circulating tumor cells are present in the blood of post-treatment cancer patients sometimes even decades later! Perhaps the niches that regulate prolonged dormancy of tumors are dynamic and inhibit tumor proliferation while allowing them to mobilize periodically, much like for HSCs. It also stands to reason that loss of the same controls that prevent HSC expansion until systemic damage occurs could awaken dormant tumors.Shiozawa et al. (2011) have demonstrated that prostate cancer cells do in fact compete with HSCs for niches within the bone marrow, and that tumor cells are mobilized from HSC niches by similar mechanisms as for HSCs. Whether this is the case for other cancers and whether these similarities can be exploited therapeutically remain to be seen.So what more is there to be learned about immune cells? By furthering our understanding of how solid cancers mimic and hijack components of our immune system, we may not “cure” cancer, but we very well may uncover a means to suppress some cancers into a state of permanent dormancy.     

Epstein-Barr virus antibodies in patients with ataxia-telangiectasia and other immunodeficiency diseases

An unusual antibody response to the Epstein—Barr virus (EBV) has been noted in patients with ataxia—telangiectasia. Of a group of 16 such patients 8 were found to have antibodies in their serum to the EBV viral capsid antigen (VCA), and 4 of them also had antibodies to the EBV early antigen (EA); antibodies to the nuclear antigen (EBNA), however, were absent in 3 of the 8. The antibody pattern persisted for more than 2 years in the patients available for follow-up study. In comparison, of 24 patients with various other immunodeficiency syndromes 9 were found to have EBV-VCA antibodies in their serum, but none of the 9 had EA antibodies and 3 lacked EBNA antibodies. Two other groups of subjects, all of whom had EBV-VCA and EBNA antibodies in their serum late after an EBV infection, were also studied; 82 had infectious mononucleosis and 55 were healthy and had no such history. EA antibodies were detected in 45 of the first group during the acute phase of the illness but persisted in only 6 of the 68 who were followed up for more than 2 years, and they were detected in only 7 of the second group.All eight lymphoblastoid cell lines established from the peripheral blood of the four patients with ataxia—telangiectasia who are still available for follow-up study express EBV-VCA, whereas most similar cell lines established from normal individuals express only EBNA. In two of these patients cell-mediated immunity, as assessed from lymphocyte transformation induced by mitogens, was markedly decreased but autologous cell-mediated immune regression of EBV-induced transformation of B (bone-marrow-derived)-lymphocytes was normal. The percentage of T (thymus-derived)-helper cells was greatly decreased in two of the three patients in whom it was measured, and the percentage of T-suppressor cells was greatly increased in one of them, but the percentage of total T-lymphocytes was within normal limits in all three.The possible significance of these findings — in particular, the persistence of EA antibodies and the diminished restriction of expression of EA — in the late development of tumours after an EBV infection in patients with ataxia-telangiectasia deserves careful attention. Finally, the apparent correlation between immunoglobulin deficiency and poor or absent EBNA antibody response warrants further study.     

Estimating the Counterfactual Impact of Conservation Programs on Land Cover Outcomes: The Role of Matching and Panel Regression Techniques

Deforestation and conversion of native habitats continues to be the leading driver of biodiversity and ecosystem service loss. A number of conservation policies and programs are implemented—from protected areas to payments for ecosystem services (PES)—to deter these losses. Currently, empirical evidence on whether these approaches stop or slow land cover change is lacking, but there is increasing interest in conducting rigorous, counterfactual impact evaluations, especially for many new conservation approaches, such as PES and REDD, which emphasize additionality. In addition, several new, globally available and free high-resolution remote sensing datasets have increased the ease of carrying out an impact evaluation on land cover change outcomes. While the number of conservation evaluations utilizing ‘matching’ to construct a valid control group is increasing, the majority of these studies use simple differences in means or linear cross-sectional regression to estimate the impact of the conservation program using this matched sample, with relatively few utilizing fixed effects panel methods—an alternative estimation method that relies on temporal variation in the data. In this paper we compare the advantages and limitations of (1) matching to construct the control group combined with differences in means and cross-sectional regression, which control for observable forms of bias in program evaluation, to (2) fixed effects panel methods, which control for observable and time-invariant unobservable forms of bias, with and without matching to create the control group. We then use these four approaches to estimate forest cover outcomes for two conservation programs: a PES program in Northeastern Ecuador and strict protected areas in European Russia. In the Russia case we find statistically significant differences across estimators—due to the presence of unobservable bias—that lead to differences in conclusions about effectiveness. The Ecuador case illustrates that if time-invariant unobservables are not present, matching combined with differences in means or cross-sectional regression leads to similar estimates of program effectiveness as matching combined with fixed effects panel regression. These results highlight the importance of considering observable and unobservable forms of bias and the methodological assumptions across estimators when designing an impact evaluation of conservation programs.     

Freelancer

What long‐term changes can we expect, in how academic work is conducted and remunerated, in the post‐pandemic world? Subject Categories: S&S: Economics & Business, S&S: History & Philosophy of Science, S&S: Ethics

Although still two years away, my looming “retirement” from university employment is inevitably going to herald a major change of life. “Of course, you''ll become ‘Emeritus’”, most colleagues have opined. My answer to all of them has been a firm “No. I''ll become a freelancer”. The concept of a freelance scientist is obviously so alien to most of them that they invariably change the subject immediately. However, my gut feeling is that in 20 years or less, almost all of us will be freelancers of some kind.The COVID‐19 pandemic has altered the world of work in very obvious ways. There has been much talk of how the changes are likely to carry over to the future, even if more traditional patterns will probably reassert themselves in the short to medium term. Working from home, conducting meetings remotely, not wasting days travelling between continents for a few precious hours of face‐time and being free to structure workdays around our own priorities: these are the most obvious novelties that many believe will continue long after the effects of the pandemic on health and wealth have faded. But I have a slightly different take.Major disruptive events of worldwide import—world wars, global economic slumps, cataclysmic volcanic eruptions and pandemics—have often been harbingers of profound social change. This is not only due to their direct and immediate effects, but more so because the disruption accelerates and facilitates changes that were already happening. In the case of COVID‐19, one may place in this category the demise of cash, the rise of streaming services in place of live entertainment, online grocery shopping and even virtual dating. Another is paying people to stay home and do nothing, otherwise known as the universal basic income (or, in the USA, “stimulus cheques”).Inefficient practices in academia are equally ripe for change. Why bother with classes for 500 first‐year students when a much better edition of the lecture by an expert communicator is available on the internet? What’s the use of an ageing PhD advisor 20 years away from bench science, who struggles to guide the next generation of experimentalists in the lab, when the expertise of a plethora of specialists can easily be accessed online? What’s the value in published papers that are read by fewer people than wrote them? Or in seminars delivered to a roomful of attentive postdocs and PhD students who lack the courage or the time to address even a single question to the speaker?Yes, there is still great value in small‐group teaching and mentorship, in the creative verve of a close‐knit laboratory team, and in good writing and oratory: but the required skills are already different from those in which we were schooled. Thus, even if I do not hold in my palm the crystal ball to predict exactly which changes will happen and how fast, I believe that our traditional jobs are going to melt away very fast in the post‐pandemic world. Universities and research institutes may still exist, but I expect that their practices will be different, reshaped by rational need more than by tradition. Today’s academic science is already quite unlike that of 1920, but it has evolved so slowly during that century—spanning a much longer time period than the lifetime of a scientific career—that we barely perceive the changes that have occurred. In contrast, the changes now afoot will certainly happen much faster, especially since the funds to support the current “inefficient” model are likely to diminish rapidly.So, I predict that university teaching and science communication in general will be the first to evolve into freelance activities, where universities will invite bids from individuals or their agents and award commissions on a fee‐paying basis rather than using salaried employees. But these are not the only component parts of academia facing such a shake‐up. The practices of laboratory science are also likely to be rebuilt. When discussing with colleagues how research might be undertaken on a freelance basis, they usually raise issues such as bricks and mortar and the complex infrastructure that is needed to sustain cutting‐edge research, especially in the life sciences: how, they ask, could a freelancer access state‐of‐the‐art imaging, mass spectrometry or DNA sequencing? How could their acquisition of such expensive hardware possibly be financed, especially if they had to somehow acquire it personally and set it up in the garage or carry it around with them?But the answers to these questions are already evident in the practices of some major research agencies, most notably in Europe’s pioneering funder of single‐investigator grants for blue‐skies science, the European Research Council (ERC). The ERC already treats its awardees as freelancers, in the sense that it encourages them to shop around for the most attractive venue in which to embed and implement their research project. The quest for the best host institution takes place not only at the preparatory step of an ERC application: it also happens after the grant is awarded, since the grant money is considered inherently portable and can even be moved later on from one institution to another. This encourages potential host universities to compete for providing the best research environment, in which many factors come into play, not just but not least, the quality of its research infrastructure. How well it supports, rather than burdens its staff with administrative tasks, the nature of its recruitment and personnel policies, how it handles relocation issues for incoming researchers and their families, what opportunities it provides for further training in relevant skills and career development: these are just some of the factors in play.In recent years, universities have seen their primary role in this process as encouraging their own tenured or tenure‐track staff to apply for ERC grants. But I foresee the emphasis shifting increasingly to investigators who seek out universities that can make the most appealing offer, whilst universities and government agencies standing behind them will shape their policies so as to remain competitive. Moreover, in such a landscape there is no reason why a scientist cannot operate research projects on multiple sites if this offers the most convenient arrangement. The tools for remote meetings and cloud computing to which we have all become accustomed mean that there is no longer any need for a research group to be located in one building or even in one country, to operate efficiently as a team.At the same time, many of the tasks involved in running a research institute or department can be efficiently outsourced to the most competitive bidder—to be assessed on the basis of value‐for‐money, not just minimum cost. As a society, we should be asking ourselves why we continue to waste the talents of highly specialized scientists on performing admin tasks for which they are neither properly trained nor motivated, instead of just engaging a smart‐software developer. Why should we fund creative thinkers to undertake laboratory projects in host institutions that do not have the required state‐of‐the‐art facilities to perform them? Or allocate budgets that are so pared down that grantholders cannot even afford to purchase such services elsewhere? Why should we expect them to make do with poorly paid trainees instead of a team of professionals? And why should we continue to organize research in pyramid structures where everything depends on commands from the top, where all findings are announced using an institutional slide template, where colleagues elsewhere are considered as untrustworthy “competitors”, and where credit for individual creativity is usurped by seniors who barely know the contents of the papers they “write”?In the “old system”, we have all gotten used to making do with sub‐optimal working arrangements and grumbling about them, whilst considering them an immutable fact of life. But I envisage a time coming soon where we scientists will have the edge in reshaping the market for teaching and research in a way that is much more to our liking and properly aligned with our skills. At the same time, our individual success in accomplishing our professional goals will have a direct effect on our income and job satisfaction, and steer us towards activities where our talents are most effectively deployed. In short, I believe that we, as freelance scientists, will be much more firmly in control of science in the future and that time is not far off.     

Beyond GLMs: A Generative Mixture Modeling Approach to Neural System Identification

Generalized linear models (GLMs) represent a popular choice for the probabilistic characterization of neural spike responses. While GLMs are attractive for their computational tractability, they also impose strong assumptions and thus only allow for a limited range of stimulus-response relationships to be discovered. Alternative approaches exist that make only very weak assumptions but scale poorly to high-dimensional stimulus spaces. Here we seek an approach which can gracefully interpolate between the two extremes. We extend two frequently used special cases of the GLM—a linear and a quadratic model—by assuming that the spike-triggered and non-spike-triggered distributions can be adequately represented using Gaussian mixtures. Because we derive the model from a generative perspective, its components are easy to interpret as they correspond to, for example, the spike-triggered distribution and the interspike interval distribution. The model is able to capture complex dependencies on high-dimensional stimuli with far fewer parameters than other approaches such as histogram-based methods. The added flexibility comes at the cost of a non-concave log-likelihood. We show that in practice this does not have to be an issue and the mixture-based model is able to outperform generalized linear and quadratic models.     

Acetanilide Oxidation in Phenylbutazone-associated Hypoplastic Anaemia

Acetanilide like phenylbutazone is paraoxidized by the liver endoplasmic reticulum as a primary biotransformation step. Both compounds were given at different times to each of 10 healthy volunteer subjects and the plasma disappearances measured. Correlation was shown between plasma clearance values of the two compounds (r = + 0·7067; P < 0·05).Eight patients with hypoplastic anaemia after phenylbutazone therapy were investigated. Plasma clearance values and half lives of acetanilide were measured in this group of patients and compared with those of a group of 30 healthy volunteer controls. There was a significant decrease in clearance (P < 0·01) and lengthening of half lives (P < 0·001 in the patients with phenylbutazone-associated hypoplasia. Five patients with idiopathic aplastic anaemia—that is, without history of antecedent phenylbutazone ingestion—were similarly investigated with acetanilide and there was no significant difference between the results in these patients and those in the control group.It is suggested that relatively poor paraoxidation of phenylbutazone producing high blood concentrations on a given dose may be a factor responsible for the drug-associated hypoplasia even though it does not explain the similar pattern of adverse reactions reported in association with oral administration of the metabolite oxyphenbutazone.     

Energetic and Dynamic: How Mitochondria Meet Neuronal Energy Demands

Mitochondria are the power houses of the cell, but unlike the static structures portrayed in textbooks, they are dynamic organelles that move about the cell to deliver energy to locations in need. These organelles fuse with each other then split apart; some appear anchored and others more free to move around, and when damaged they are engulfed by autophagosomes. Together, these processes—mitochondrial trafficking, fusion and fission, and mitophagy—are best described by the term “mitochondrial dynamics”. The molecular machineries behind these events are relatively well known yet the precise dynamics in neurons remains under debate. Neurons pose a peculiar logistical challenge to mitochondria; how do these energy suppliers manage to traffic down long axons to deliver the requisite energy supply to distant parts of the cell? To date, the majority of neuronal mitochondrial dynamics studies have used cultured neurons, Drosophila larvae, zebrafish embryos, with occasional experiments in resting mouse nerves. However, a new study in this issue of PLOS Biology from Marija Sajic and colleagues provides an in vivo look at mitochondrial dynamics along resting and electrically active neurons of live anaesthetized mice.     

A Vivens Ex Vivo Study on the Synergistic Effect of Electrolysis and Freezing on the Cell Nucleus

Freezing—cryosurgery, and electrolysis—electrochemical therapy (EChT), are two important minimally invasive surgery tissue ablation technologies. Despite major advantages they also have some disadvantages. Cryosurgery cannot induce cell death at high subzero freezing temperatures and requires multiple freeze thaw cycles, while EChT requires high concentrations of electrolytic products—which makes it a lengthy procedure. Based on the observation that freezing increases the concentration of solutes (including products of electrolysis) in the frozen region and permeabilizes the cell membrane to these products, this study examines the hypothesis that there could be a synergistic effect between freezing and electrolysis in their use together for tissue ablation. Using an animal model we refer to as vivens ex vivo, which may be of value in reducing the use of animals for experiments, combined with a Hematoxylin stain of the nucleus, we show that there are clinically relevant protocols in which the cell nucleus appears intact when electrolysis and freezing are used separately but is affected by certain combinations of electrolysis and freezing.     

CEE-ing is believing: Bioscience ventures in Central and Eastern Europe

Bioscience ventures in Central and Eastern Europe are becoming a presence in world healthcare markets despite a perennially short supply of venture funding and other support mechanisms relative to other world economic regions. Here are three up-and-coming CEE stories worth keeping an eye on.Innovations in bioscience happen every day all over the world—in laboratories, on university campuses, in rich and poor nations alike—coming to life somewhere in the minds of inspired scientists who think they just might have a breakthrough solution to some daunting healthcare problem. The vast majority of these innovations, unfortunately, never make it to commercial markets, where they could be applied to solve actual medical challenges. This is true for a variety of reasons: intellectual property stuck in the recesses of academia; lack of practical know-how in running a business on the part of the innovators; but perhaps most of all because of the absence, in most parts of the world, of a supporting ecosystem of institutions and individuals that encourage and invest in highly risky early stage opportunities. There are very few localities that can replicate the intellectual know-how and financial resources on tap in places like Silicon Valley, and for all that the world economy has globalized over the last twenty years, venture capital is still very much a local backyard business.That being said, there are stories out there demonstrating that you don''t have to live in Palo Alto and sign a major venture capital backer to bring a worthwhile idea into fruition, establish a solid commercial value proposition and position yourself on a potentially robust growth trajectory. This article is about three such stories. The common thread between them is that they all took root in Central and Eastern Europe. This is a region with a relatively short history of modern free market economics and plenty of bumps in the road since the Berlin Wall came down in 1989 but at the same time one that retains a longstanding tradition of commitment to research and scientific excellence. Now the knowledge and expertise resident in what was once the bleak landscape stuck behind the Iron Curtain has the potential to help solve important healthcare challenges the world over. The founders of these three companies—an eclectic group of individuals from different backgrounds who perceived opportunities and accepted the daunting risks involved in choosing to pursue them—have brought themselves into a position where they may yet reap significant rewards for their labors.     

When cooperation begets cooperation: the role of key individuals in galvanizing support

Life abounds with examples of conspecifics actively cooperating to a common end, despite conflicts of interest being expected concerning how much each individual should contribute. Mathematical models typically find that such conflict can be resolved by partial-response strategies, leading investors to contribute relatively equitably. Using a case study approach, we show that such model expectations can be contradicted in at least four disparate contexts: (i) bi-parental care; (ii) cooperative breeding; (iii) cooperative hunting; and (iv) human cooperation. We highlight that: (a) marked variation in contributions is commonplace; and (b) individuals can often respond positively rather than negatively to the contributions of others. Existing models have surprisingly limited power in explaining these phenomena. Here, we propose that, although among-individual variation in cooperative contributions will be influenced by differential costs and benefits, there is likely to be a strong genetic or epigenetic component. We then suggest that selection can maintain high investors (key individuals) when their contributions promote support by increasing the benefits and/or reducing the costs for others. Our intentions are to raise awareness in—and provide testable hypotheses of—two of the most poorly understood, yet integral, questions regarding cooperative ventures: why do individuals vary in their contributions and when does cooperation beget cooperation?     

Comparative Study of District and Community Hospitals

Opinions conflict on whether there is a place in the Health Service for general practitioner (community) hospitals in which the patients'' treatment is mainly the responsibility of their family doctors. The authors therefore analysed a sample of the patients admitted in the course of a year to a group of two general district hospitals with a comparable sample of the patients admitted to a general practitioner hospital. The aim was to analyse the type of care provided in the general practitioner hospital, to assess whether it was appropriate for the type of cases treated, and to decide whether the patients would have been better off in the district general hospital (and vice versa). The main conclusions are that a district hospital is best for serious illnesses needing skilled decisions and assessments but that most of the work of these hospitals is not of this kind and a community hospital staffed by general practitioners offers many advantages to patients—provided the work being done is constantly under critical assessment. The authors plead for special refresher courses under the N.H.S. for general practitioners working in community hospitals.     

Borrowed robes

Should scientists indulge their fantasies by writing fiction? Subject Categories: Careers, Economics, Law & Politics, History & Philosophy of Science

Like a substantial fraction of the literate population, I have a collection of unpublished novels in the drawer. Six of them in fact. Some of them were composed in barely more than a week, and others I have been struggling to complete for over 10 years: so maybe it is more accurate to say five and a half. Anyhow, most of them are good to go, give or take a bit of editorial redlining. Or, as my helpful EMBO editor would say, the removal of thousands of unnecessary adverbs and dubiously positioned commas.What do I write about and why? My style is not unique but rather particular. I write fiction in the style of non‐fiction. My subject matter is somewhere in the general realms of science fiction, alternate history and political drama. Putting these ingredients together, and taking account of my purported day job as a serious scientist, it is easy to see why my fictional work is potentially subversive—which is one reason why I have been rather reluctant thus far to let it out of the drawer. At the very least, I should take pains to conceal my identity, lest it corrupts perceptions of my scientific work. Even if I regularly tell my students not to believe everything they read, it would impose far too great a burden on them if they came to question my peer‐reviewed articles purely on the basis of untrue statements published in my name, spoken by jaded politicians, washed‐up academics or over‐credulous journalists. Even if they are imaginary. Real journalists are theoretically bound by strict rules of conduct. But imaginary ones can do whatever they like.Today, I noticed a passage in one of these unpublished works that is clearly written in the style of a young William Shakespeare, dealing with a subject matter that fits neatly into one of his most famous plays. In fact, the illusion was such that I was sure I must have lifted the passage from the play in question and set about searching for the quote, which I then could and should cite. Yet, all Internet searches failed to find any match. The character in whose mouth I placed the words was depicted as being in a delirious state where the boundaries of fact and fiction in his life were already blurred; borrowed identities being one of the themes of the entire novel and arguably of my entire oeuvre. But am I guilty here of plagiarism or poetry, in adopting the borrowed identity of my national playwright?In another work, I lay great emphasis on the damaging role of mitochondrial reactive oxygen species (ROS) as the cause of biological ageing. I have even grafted this explanation onto a thinly disguised version of one of my most valued colleagues. Although there is some support for such a hypothesis from real science, including some papers that I have myself co‐authored, it is also a dangerously broad generalization that leads easily into wrong turnings and misconstructions—let alone questionable policies and diet advice. But, by advancing this misleading and overly simplistic idea in print, have I potentially damaged not only my own reputation, but that of other scientists whom I respect? Even if the author’s identity remains hidden.In one novel, I fantasize that nuclear weapons, whilst they do undoubtedly exist, have in fact been engineered by their inventors so as never actually to work, thus preventing their possible misuse by vainglorious or lunatic politicians unconcerned with the loss of millions of lives and planetary ruin. But if any insane national leader—of which there are unfortunately far too many—would actually come to believe that my fiction in the style of non‐fiction were true, they might indeed risk the outbreak of nuclear war by starting a conventional one in order to secure their strategic goals.Elsewhere, I vindicate one author of published claims that were manifestly based on falsified data, asserting him to have instead been the victim of a conspiracy launched to protect the family of an otherwise much respected American President. None of which is remotely true. Or at least there is no actual evidence supporting my ridiculous account.I have great fun writing fiction of this kind. It is both liberating and relaxing to be able to ignore facts and the results of real experiments and just invent or distort them to suit an imaginary scenario. In an age when the media and real politicians have no qualms about propagating equally outrageous “alternative facts”, I can at least plead innocent by pointing out that my lies are deliberate and labelled as such, even if people might choose to believe them.In a further twist, the blurb I have written to describe my latest work characterizes it as the “semi‐fictionalized” biography of a real person, who was, in fact, a distant relative of mine. But if it is semi‐fictionalized, which bits are true and which are made up? Maybe almost the whole thing is invented? Or maybe 99% of it is based on demonstrable facts? Maybe the subject himself concocted his own life story and somehow planted it in falsified documents and newspaper articles to give it an air of truth. Or maybe the assertion that the story is semi‐fictionalized is itself a fictional device, that is, a lie. Perhaps the central character never existed at all.It is true (sic) that the most powerful fiction is grounded in fact—if something is plausible, it is all the more demanding of our attention. And, it can point the way to truths that are not revealed by a simple catalogue of factual information, such as in a scientific report.But I have already said too much: if any of my novels ever do find their way into print, and should you chance to read them, I will be instantly unmasked. So maybe I’ll have to slot in something else in place of my pseudo‐Shakespearean verse, mitochondrial ROS hypothesis, defunct weapons of mass destruction and manipulated data manipulation.     

Milestone Age Affects the Role of Health and Emotions in Life Satisfaction: A Preliminary Inquiry

Jill turns 40. Should this change how she evaluates her life, and would a similar change occur when she turns 41? Milestone age (e.g., 30, 40, 50)—a naturally occurring feature in personal timelines—has received much attention is popular culture, but little attention in academic inquiry. This study examines whether milestone birthdays change the way people evaluate their life. We show that life outlook is impacted by this temporal landmark, which appears to punctuate people’s mental maps of their life cycle. At these milestone junctures, people take stock of where they stand and have a more evaluative perspective towards their lives when making life satisfaction judgments. Correspondingly, they place less emphasis on daily emotional experiences. We find that milestone agers (vs. other individuals) place greater weight on health satisfaction and BMI and lesser weight on daily positive emotions in their overall life satisfaction judgments, whereas negative emotions remain influential.     

The theoretical and political framing of the population factor in development

The silence about population growth in recent decades has hindered the ability of those concerned with ecological change, resource scarcity, health and educational systems, national security, and other global challenges to look with maximum objectivity at the problems they confront. Two central questions about population—(i) is population growth a problem? and (2) what causes fertility decline?—are often intertwined; if people think the second question implies possible coercion, or fear of upsetting cultures, they can be reluctant to talk about the first. The classic and economic theories explaining the demographic transition assume that couples want many children and they make decisions to have a smaller family when some socio-economic change occurs. However, there are numerous anomalies to this explanation. This paper suggests that the societal changes are neither necessary nor sufficient for family size to fall. Many barriers of non-evidence-based restrictive medical rules, cost, misinformation and social traditions exist between women and the fertility regulation methods and correct information they need to manage their family size. When these barriers are reduced, birth rates tend to decline. Many of the barriers reflect a patriarchal desire to control women, which can be largely explained by evolutionary biology. The theoretical explanations of fertility should (i) attach more weight to the many barriers to voluntary fertility regulation, (ii) recognize that a latent desire to control fertility may be far more prevalent among women than previously understood, and (iii) appreciate that women implicitly and rationally make benefit–cost analyses based on the information they have, wanting modern family planning only after they understand it is a safe option. Once it is understood that fertility can be lowered by purely voluntary means, comfort with talking about the population factor in development will rise.     

Distribution of proteins between nucleus and cytoplasm of amoeba proteus

By transplanting nuclei between labeled and unlabeled cells, we determined the localization of the major proteins of amebas and described certain features of their intracellular distributon. We identified approximately 130 cellular proteins by fluorography of one-dimensional polyacrylamide electrophoretic gels and found that slightly less than half of them (designated NP, for nuclear proteins) are almost exclusively nuclear. About 95 percent of the other proteins (designated CP for cytoplamsic proteins) are roughly equally concentrated in nucleus and cytoplasm, but—because the cytoplasm is 50 times larger than the nucleus—about 98 percent of each of the latter is in the cytoplasm. Of the CP, roughly 5 percent are not detectable in the nucleus. Assuming that these are restricted to the cytoplasm only because, for example, they are in structures too large to enter the nucleus and labeled CP readily exit a nucleus introduced into unlabeled cytoplasm, we conclude that the nuclear envelope does not limit the movement of any nonstructural cellular protein in either direction between the two compartments. Some NP are not found in the cytoplasm (although ostensibly synthesized there) presumably because of preferential binding within the nucleus. Almost one half of the protein mass in nuclei in vivo is CP and apparently only proteins of that group are lost from nuclei when cells are lysed. Thus, while an extracellular environment allows CP to exit isolated nuclei, the nuclear binding affinities for NP are retained. Further examination of NP distribution shows that many NP species are, in fact, detectable in the cytoplasm (although at only about 1/300 the nuclear concentration), apparently because the nuclear affinity is relatively low. These proteins are electrophoretically distinguishable from the high-affinity NP not found in the cytoplasm. New experiments show that an earlier suggestion that the nuclear transplantation operation causes an artifactual release of NP to the cytoplasm is largely incorrect. Moreover, we show that cytoplasmic “contamination” of nuclear preparations is not a factor in classifying proteins by these nuclear transplantation experiments. We speculate the no mechanism has evolved to confine most CP to the cytoplasm (where they presumably function exclusively) because the cytoplasm’s large volume ensures that CP will be abundant there. Extending Bonner’s idea of “quasi-functional nuclear binding sites” for NP, we suggest that a subset of NP usually have a low affinity for available intranuclear sites because their main function(s) occurs at other intranuclear sites to which they bind tightly only when particular metabolic conditions demand. The other NP (those completely absent from cytoplasm) presumable always are bound with high affinity at their primary functional sites.     

Revisiting the importance of model fitting for model-based fMRI: It does matter in computational psychiatry

Computational modeling has been applied for data analysis in psychology, neuroscience, and psychiatry. One of its important uses is to infer the latent variables underlying behavior by which researchers can evaluate corresponding neural, physiological, or behavioral measures. This feature is especially crucial for computational psychiatry, in which altered computational processes underlying mental disorders are of interest. For instance, several studies employing model-based fMRI—a method for identifying brain regions correlated with latent variables—have shown that patients with mental disorders (e.g., depression) exhibit diminished neural responses to reward prediction errors (RPEs), which are the differences between experienced and predicted rewards. Such model-based analysis has the drawback that the parameter estimates and inference of latent variables are not necessarily correct—rather, they usually contain some errors. A previous study theoretically and empirically showed that the error in model-fitting does not necessarily cause a serious error in model-based fMRI. However, the study did not deal with certain situations relevant to psychiatry, such as group comparisons between patients and healthy controls. We developed a theoretical framework to explore such situations. We demonstrate that the parameter-misspecification can critically affect the results of group comparison. We demonstrate that even if the RPE response in patients is completely intact, a spurious difference to healthy controls is observable. Such a situation occurs when the ground-truth learning rate differs between groups but a common learning rate is used, as per previous studies. Furthermore, even if the parameters are appropriately fitted to individual participants, spurious group differences in RPE responses are observable when the model lacks a component that differs between groups. These results highlight the importance of appropriate model-fitting and the need for caution when interpreting the results of model-based fMRI.